1. Field of the Invention
The invention relates to a novel use of Glycyrrhiza inflata (G. inflata) extract in treatment of neurodegenerative disorders. Particularly, the invention relates to the use of ammonium glycyrrhizinate (AMGZ) and licochalcone A contained in the extract in treating polyglutamine (polyQ)-mediated spinocerebellar ataxia (SCA).
2. Description of Related Art
Most age-related neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are characterized by accumulation of aberrant protein aggregates/inclusions in the affected brain regions. Among them, SCA types 1, 2, 3, 6, 7, 8, 17, and dentatorubropallidoluysianatrophy (DRPLA) as well as Huntington's disease (HD) are a group of neurodegenerative disorders caused by expanded CAG repeats encoding a long polyQ tract in the respective proteins. The polyQ-mediated SCAs have shown selective progressive degeneration of the cerebellum, brainstem, and spinal tract, with pathological hallmark of intranuclear and cytoplasmic aggregates. Impaired proteasome and autophagy activity, transcriptional dysregulation, oxidative stress, and mitochondrial dysfunction have been shown to play important roles in the pathogenesis of polyQ-mediated diseases. Increasingly substantial evidence has shown that aggregate formation promoted by misfolding of the polyQ protein is likely the initial process to trigger the subsequent pathological events. Therefore, agents that can prevent the aggregate formation or promote the degradation of aggregates may possess the great potential to treat the polyQ diseases.
Peroxisome proliferator-activated receptor gamma, coactivator 1 alpha (PPARGC1A) is a known regulator of mitochondrial biogenesis and anti-oxidative response genes, such as superoxide dismutase 2 (SOD2) and mitochondrial and cytochrome c, somatic (CYCS). PPARGC1A null mice developed spongiform neurodegeneration in selective brain areas, which indicated the direct role of PPARGC1A in neurodegeneration. Transcriptional repression of PPARGC1A by mutant huntington leading to mitochondrial dysfunction and neurodegeneration has also been shown in HD mouse models, suggesting that agents enhancing the transcriptional activity of PPARGC1A may be the potential therapeutics for HD and other polyQ diseases.
Increased oxidative damage plays an important role in the pathogenesis of SCA1, SCA2, SCA3, SCAT, SCA17, HD, and other expanded polyQ diseases. Anti-oxidants have been shown to be the potential therapeutics for SCA1, SCA17 and HD. The nuclear factor erythroid 2-related factor 2 (NFE2L2) and the antioxidant response elements (AREs) signaling pathway is regarded as the most important in the cell to protect against oxidative stress. The principal transcription factor NFE2L2 binds to AREs and recruits the general transcriptional machinery for ARE-dependent gene expression when the cells respond to oxidative stress. The endogenous phase II anti-oxidative enzymes, heme oxygenase (decycling) 1 (HMOX1), NAD(P)H dehydrogenase, quinone 1 (NQO1), glutamate-cysteine ligase catalytic subunit (GCLC), and glutathione S-transferase pi 1 (GSTP1) are among the target genes regulated by NFE2L2. NFE2L2 plays a neuroprotection role in the MPTP mouse model of PD. Mutant huntington disrupts NFE2L2 signaling, which contributes to impaired mitochondrial dynamics and may enhance susceptibility to oxidative stress in a HD cell model. PPARGC1A was recently found to also regulate the transcription of NFE2L2. Therefore, we proposed that compounds that can activate PPARGC1A and/or NFE2L2 may be beneficial to SCA3 and other polyQ diseases. The roots of licorice (Glycyrrhiza) species have long been used as an herbal medicine to treat peptic ulcer, hepatitis C, diabetes, and pulmonary and skin diseases. G. inflata is one of Glycyrrhiza species. Licochalcone A and glycyrrhizin, two major constituents of G. inflata have recently been reported to have anti-oxidative, anti-inflammatory, anti-microbial as well as neuroprotective effects.
Although there are prior art references disclosing relationship between the anti-oxidants and SCAs, none of them is relevant to the G. inflata extract and the correlation of G. inflata extract with SCAs remains unclear. Therefore, it is beneficial to develop a medicament based on G. inflata for treatment of neurodegenerative disorders.